Identification of a genotoxic mechanism for 2-nitroanisole carcinogenicity and of its carcinogenic potential for humans
Language English Country Great Britain, England Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
14729594
DOI
10.1093/carcin/bgh061
PII: bgh061
Knihovny.cz E-resources
- MeSH
- DNA Adducts * MeSH
- Aldehyde Oxidase metabolism MeSH
- Aniline Compounds metabolism MeSH
- Anisoles pharmacokinetics toxicity MeSH
- Cytosol enzymology MeSH
- Child MeSH
- DNA metabolism MeSH
- Adult MeSH
- Phosphorus Isotopes * MeSH
- Liver drug effects enzymology MeSH
- Carcinogens pharmacokinetics toxicity MeSH
- Rats MeSH
- Kidney drug effects enzymology MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Urinary Bladder drug effects enzymology MeSH
- NAD(P)H Dehydrogenase (Quinone) metabolism MeSH
- Rats, Wistar MeSH
- Child, Preschool MeSH
- Aged MeSH
- Spleen drug effects enzymology MeSH
- Xanthine Oxidase metabolism MeSH
- Animals MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Rats MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Child, Preschool MeSH
- Aged MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 2-anisidine MeSH Browser
- 2-nitroanisole MeSH Browser
- DNA Adducts * MeSH
- Aldehyde Oxidase MeSH
- Aniline Compounds MeSH
- Anisoles MeSH
- DNA MeSH
- Phosphorus Isotopes * MeSH
- Carcinogens MeSH
- NAD(P)H Dehydrogenase (Quinone) MeSH
- NQO1 protein, human MeSH Browser
- Xanthine Oxidase MeSH
2-Nitroanisole (2-NA) is an important industrial pollutant and a potent bladder carcinogen for rodents. The mechanism of its carcinogenicity was investigated in this study. Here we have used two independent methods, (32)P-post-labeling and (3)H-labeled 2-NA, to show that 2-NA binds covalently to DNA in vitro after reductive activation by human hepatic cytosol and xanthine oxidase (XO). We also investigated the capacity of 2-NA to form DNA adducts in vivo. Male Wistar rats were treated i.p. with 2-NA (0.15 mg/kg body wt daily for 5 days) and DNA from several organs was analyzed by (32)P-post-labeling. Two 2-NA-specific DNA adducts, identical to those found in DNA incubated with 2-NA and human hepatic cytosol or XO in vitro, were detected in the urinary bladder (3.4 adducts/10(7) nt), the target organ, and, to a lesser extent, in liver, kidney and spleen. The two DNA adducts found in rat tissues in vivo were identified as deoxyguanosine adducts derived from a 2-NA reductive metabolite, N-(2-methoxyphenyl)hydroxylamine. This reactive metabolite of 2-NA was identified in incubations with human hepatic cytosol, besides 2-methoxyaniline (o-anisidine). The results of our study, the first report on the potential of human cytosolic enzymes to contribute to the activation of 2-NA by nitroreduction, strongly suggest a carcinogenic potency of this rodent carcinogen for humans.
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